Atherosclerotic cardiovascular disease remains the leading cause of mortality in the United States. Coronary artery disease (CAD) comprises 60% of deaths from atherosclerotic cardiovascular disease and places an enormous burden on the healthcare system. Although drug-coated-stenting has become the primary intervention of CAD, recent warning by the FDA has indicated that all patients receiving the drug-coated devices are at a heightened risk for blood clots, and that many patients receiving the devices are at risk for heart attacks and death. Thus, it is essential to explore alternative approaches to manage CAD. Gene therapy shows great potential for treatment of the causes of CAD. In recent years, supported by a 4-year NIH R01 grant, we have successfully proven the principle of a novel concept intravascular MR- imaging/radiofrequency (RF)-enhanced vascular gene therapy. This new technology can now be applied to the treatment of CAD. Extending this new technology to coronary arteries, we will explore two novel technical developments, including (a) an intracoronary MR-imaging/RF-heating system to simultaneously generate high-resolution MR imaging of the gene/stent-targeted coronary arteries and MR/RF-enhanced gene transduction/expression in the coronary arteries;and (b) intracoronary MR/RF-enhanced gene therapy of in-stent stenosis. These novel techniques will be validated in a series of preclinical studies in the coronary arteries of near-human-sized animals, domestic pigs and Yucatan miniature pigs with CAD, which should facilitate the further translation of these novel techniques from the benchside to the bedside. We firmly believe that the success of this project will establish the groundwork for our longer-term goal of applying MR-based vascular gene therapy to efficiently treat CAD in humans. Project Narrative: Atherosclerotic cardiovascular disease (ACD) remains the leading cause of mortality in the United States, and places an enormous burden on the healthcare system. To day, the method for efficient treatment of ACD has not been established. In the current proposal, we will explore a novel technology - intracoronary MRI-based, radiofrequency (RF)-enhanced gene therapy of ACD. The success of this project should open up new avenues for the future global comprehensive management of ACD using MR-based modalities.